Osteoporosis is a major public health problem especially in the aging population. Uric acid may affect bone health. Recent evidence indicates that uric acid serves as an endogenous antioxidant at normal physiological ranges (3-7 mg/dL) and it has been associated with higher bone mineral density, lower bone turnover and lower prevalence of fractures in a large cross-sectional study of men. However, at elevated levels (hyperuricemia), uric acid may act as a prooxidant and contribute to inflammation. Oxidative stress and inflammation has been implicated as one of the etiologic pathways involved in bone loss. However, associations of elevated uric acid level with bone have not been studied. Vitamin C intake has a uricosuric effect. Therefore vitamin C may contribute to maintenance of uric acid concentrations in the normal physiological range, thereby supporting an antioxidant effect instead of a prooxidant effect on bone. Our previous work demonstrated that vitamin C (a powerful water soluble antioxidant) protects against bone loss and risk of hip fracture. Yet surprisingly not much is known about the inter-relation of vitamin C and uric acid with osteoporosis. Uric acid may provide a unique yet unexplored mechanism through which vitamin C may affect bone health. The proposed work will be able to examine the relation between uric acid concentrations in the normal range with bone health as well as potential deleterious effects of high levels of uric acid, which has not been previously studied. Therefore, the specific goal is to examine the relation of serum uric acid and bone health and to determine whether vitamin C may represent an important part of the potential biologic pathway involving uric acid and bone. The participants from the Framingham Original cohort and Generation Three (Gen3) cohort will comprise the study sample for the proposed grant. Of the cohort members, 3,003 men and women had serum uric acid samples collected and were followed for hip fracture. Of the Gen3 cohort, 1,781 men and women had vitamin C intake, serum uric acid and QCT bone measured at the same exam. We will use mediation/suppression analysis to examine if serum uric acid mediates the association of vitamin C intake with QCT bone measures in the Gen3 cohort. The results from this study have important clinical implications because hyperuricemia can be treated with drugs and dietary modification. This could provide new therapeutic strategies to decrease risk of osteoporosis. Furthermore, findings from this proposed R03 have the potential to lead to future intervention trials in older adults.